Sialic acid-binding immunoglobulin-like lectins (Siglec(s)) are I-type lectins that are expressed by a number of cells including cells of the haematopoietic system. The Siglecs comprise a number of families of molecules, each characterised by the presence of a N-terminal V-set Ig-like domain, which mediates sialic acid binding, followed by varying numbers of C2-set Ig-like domains4.
CD33 and the CD33 related siglecs encompass eight of the 11 human siglecs. These molecules share a high degree of sequence similarity and show significant differences in composition amongst mammalian species. The genes encoding these receptors are clustered on chromosome 19q13.3-13.4 and appear to be predominantly expressed in the haematopoietic and immune systems and exhibit differential expression patterns on most mature cells of the innate immune system including monocytes, macrophages, natural killer cells, neutrophils, eosinophils, basophils, mast cells and dendritic cells6-14. All human CD33-related siglecs possess a conserved membrane proximal immunoreceptor tyrosine-based inhibition motif (ITIM), as well as a membrane distal ITIM-like motif in their cytoplasmic tails5.
Acute myeloid leukaemia (AML) describes a group of related haematological malignancies resulting from the abnormal proliferation and differentiation of haematopoietic stem cells (HSC) or progenitor cells1. In AML, cells fail to differentiate to normal mature blood cells and instead, proliferate uncontrollably. The resulting immature myeloid cells or blast cells, accumulate and rapidly replace bone marrow leading to a decrease in production of red blood cells, white blood cells and platelets. The loss of red blood cells may lead to complications such as anaemia, infection and bleeding. In some cases the blast cells occasionally invade the lymphatic system, spleen or other vital organs.
AML is classified using a combination of morphological and genetic features, with classification evolving from the French-American-British (FAB)2 to the World Health Organisation3 systems. This classification system describes the differentiation status of the predominant leukaemic (blast) cells. The degree of differentiation increases with the subtypes M0, M1, M2 and M3, while subtypes M4 and M5 are mostly monocytic in lineage and types M6 and M7 have features of erythrocytes and megakaryocytes respectively27.
Leukaemia may be described as abnormal haematopoietic tissue that is initiated by a leukaemic stem cell (LSC) that undergoes an aberrant and poorly regulated process of organogenesis, analogous to that of the normal haematopoietic stem cells (HSC). At present normal haematopoietic stem cells are regarded as CD34+, CD33−, CD38−, CD71−, CD117+/−, CD123−, Lin− while the LSC are regarded as CD34+, CD33+/−, CD38−, CD71−, CD117+/−, CD123+, Lin−. Mutations in the HSC or early progenitors lead to the development of the LSC, which has self renewal capacity. The LSC gives rise to progenitor cells which proliferate and differentiate to leukaemic blast cells.
The exclusive presence of CD33 on AML cells provides a useful marker for the detection of AML cells and a target for antibody based therapies. Mylotarg® is a humanized anti CD33 monoclonal antibody coupled to the potent antibiotic Calicheamicin-γ1 which has been approved for the treatment of relapsed AML following chemotherapy.
The present invention is based upon the observation by the inventors that the CD-33 related Siglec, Siglec-9 is absent from normal bone marrow myeloid progentitor but expressed in AML and as such provides a potential new target for therapies against cell proliferation and/or differentiation disorders. In particular it is noted that Siglec-9 is expressed on subsets of AML cells associated with severe disease (M4 and M5 FAB classification). Furthermore it has been found that unlike CD33 and Siglec-5, the levels of Siglec-9 in the bone marrow plasma were low or undetectable.
It is among the objects of the present invention to provide additional means of treating cell proliferation and or differentiation disorders, for example, acute myeloid leukaemia, and which mitigate or obviate the problems associated with the prior art.